Dec., 1944
NOTES
2127
by weight of substrate) a t 40 atmospheres of pressure. The applicability and high efficiency of the recently developed noble metal synthetic high polymer catalysts, described in previous p a p e r ~ ~ . ~ #suggested 'J' that hydrogenation be attempted employing this type of catalyst. A palladium-polyvinyl alcohol (Pd-PVA) catalyst was prepared wherein the palladium was 0.5% by weight of substrate and cyanoacetic ethyl ester was successfully hydrogenated a t atmospheric pressure.
sophical Society. Analyses were performed by Mr. Joseph Alicino of the Squibb Institute for Medical Research, New Brunswick, N. J.
Procedure The Pd-PVA catalyst was composed of 30 mg. of P d and 500 mg. of PVA in 100 cc. of 5Oy0alcohol-water mixture which was 0.5 11 in hydrochloric acid. The purpose of the high acidity was to minimize formation of secondary amines.' Six and four-tenths g. of cyanoacetic ester was introduced into the vessel with the catalyst and the whole shaken for twenty hours a t room temperature and ordinary pressure. At the end of this time 1822 cc. of a theoretical 2580 cc. of hydrogen had been adsorbed. The rate of adsorption was very slow a t this point, so the isolation of 8-alanine was started. The colloidal catalyst was flocculated by addition of about 500 cc. of ethanol. After filtering, the liquid was concentrated. Hereafter, a separation into two layers was noticed, the lower layer containing some unreduced starting material, which is insoluble in water. The latter was drawn off and to assure complete removal of unreduced cyanoacetic ethyl ester, the remaining aqueous layer was extracted twice with ether. The aqueous solution was then taken to dryness under reduced pressure. The residual salt was twice extracted with 35-cc. portions of hot 95% ethanol, filtered while hot and allowed t o cool. On cooling crystallization of ammonium chloride, which had been extracted along with the &alanine ethyl ester hydrochloride, occurred. This was filtered off and discarded. The filtrate was again evaporated t o dryness in vacuo. The residual salt was extracted with 35-cc. portions of absolute ethanol and filtered. The filtrate was concentrated in vacuo and then diluted with about 20 cc. of water and hydrolyzed under reflux. After concentrating under reduced pressure to remove the excess hydrochloric acid, the residue was dissolved in water and made up to a v01ume of 30 cc. A 2-cc. portion was withdrawn for determination of total halide.' A suspension of silver pxide prepared from 10% more than the equivalent quantity of silver nitrate was added t o the solution t o bring about complete precipitation of halide. After standing for some time, the precipitate was filtered, the filtrate concentrated and treated with hydrogen sulfide. The silver sulfide is centrifuged off, the solution treated with norite and filtered. The crystals of &alanine may be obtained by concentrating the filtrate in a vacuum desiccator until crystallization begins. Upo; recrvstallization from water a Droduct of m. D. 194-196 was. obtained with the analyks calculated:- N, 15.73; found: N, 15.56; yield, 15%. No attempt was made to increase this yield as the primary purpose of the experiments was to demonstrate the ability of the colloidal noble metal synthetic high polymer catalysts to serve in the reduction of the nitrile group.
Sulfuryl chloride is being used increasingly as a chlorinating agent because of the ease with which it reacts and the high yields obtained. I n 1939, Kharasch and Brown' treated fluorene with this reagent and reported that the fluorene was chlorinated in the nucleus. However, they did not report the position taken by the entering chlorine atom, nor did they give any yields or procedures. The purpose of this work was to determine the position of the entering chlorine and to find out whether this method is a convenient one for preparing the chloro compound. The fluorene was chlorinated in ether solution with a slight excess of sulfuryl chloride. The product melted a t 95-96O.* This compares favorably with the 2-chlorofluorene prepared simultaneously by Chanussota and Courtot and Vignati,' m. p. 96-97'. Authentic 2-chlorofluorene was prepared by the method of Chanussota from 2-aminofluorene by the Sandmeyer reaction. A mixed melting point determination showed the two to be identical. The following procedure is recommended as a quick, convenient method for preparing 2-chlorofluorene.
Acknowledgment.-These hydrogenations were carried out with the aid of. grants of the Bache Fund of the National Academy of Sciences and the Penrose Fund of the American Philo(2) Louis D. Rampino and F. F. Nord, THISJOIJENAL, 68, 2746, 3268 (1941). (3) Rampino and Nord, ibid., 66, 429 (1943). (4) Kevin E. Ravanagh, i b i d , , 64, 2721 (1942). (5) Kevin E. Kavanagh and F. F. Nord, ibid., 66, 2121 (1943). (6) "Organic Syntheses," Vol. 16, John Wiley and Son, lac., New York. N. Y..1936. p 1.
COMMUNICATION No. 36 FROM TEE PRPARTMENT OF ORGANIC CHEMISTRY FORDHAM UNIVERSITY SEPTEMBER 22, 1944 NEW YORK58, N. Y. RECEIVED
Chlorination of Fluorene with Sulfuryl Chloride BY ANDREWSTREITWIESBR
Experimental 2-Chlorofluorene from SOtClt.--Sixteen grams of fluorene and 120 cc. of anhydrous ether was placed in a distilling flask. Not all of the fluorene dissolved. The flask was stoppered with a rubber stopper carrying a separatory funnel containing 8 cc. (13.4 9 . ) sulfuryl chloride. The latter was added rapidly to the solution. When all was added, the ether was distilled off, and the residue recrystallized from alcohol. I t can also be purified by steam distillation: yield, 85% of a white crystalline powder, m. p. 95-96'. The author wishes to ackhowledge the assistance of Mr. L. Friedman and Mr. E. Kosower in this work. (1) Kharasch and Brown, THISJOURNAL, 61, 2149 (1939). (2) All melting points corrected. (3) Chanussot, Aiiales asocn. quim. Argentina, 16, 216 (1927). (4) Courtot and Vignati, Compt. rend., 184, 1479 (1927).
80-29 1 6 9 STREET ~ ~ JAMAICA 3, N. Y.
RECEIVED OCTOBER 13, 1944
The Preparation of N-Alkyl Derivatives of 9Aminobenzoic Acid' BY A. R. SURREY AND H. F. HAMMER
It has been reported' that procaine hydrochloride and other local anesthetics which are (1) Presented before t h e Division of Medicinal Chemistry, A. C. S., Cleveland, Ohio, April, 1944.
2128
NOTES
PROPERTIES AND Yield,
Alkyl
I I1 I11 IV V VI
Ethyl" n-Propyl n-Butyl Ethyl n-Propylb n-Butyl'
Vol. 66
TABLE I ANALYSES OF COMPOUNDS Nitrogen,d % Calcd. Found
Nitroso deriv. M. p., 'C.
Nitrogen, % ' Calcd. Found
%
M. p., 'C.
41 30 47
138-139 61-62 104-105
Methyl p-Alkylaminobenzoates CioHisNOi 7.82 7.93 CiiH16NOz 7.25 7.36 CizHiINOz 6.76 6.51
72-73 52-53
13.48 12.61
13.22 12.66
72-73 68-69 6&69
Ethyl p-Alkylaminobenzoates CiiHit"z 7.25 7.43 C12HuN02 6.76 6 72 CiaHi9NOz 6.33 6.49
55-56 54-55
12.61 11.88
12.74 12.14
50 45 80
Formula
.....
.....
...
f
.
.
.
.
...
...
p -Alkylaminobenzamides VI1
Ethyl
39 CgHizNz0 144-146 17.08 16.90 187-188 21.76 21.90 54 CioHirNzO 15.73 15.95 137-138 177-178 20.28 20.59 IX %-Butyl 60 C i i H i ~ N ~ O 14.58 14.60 111-112 179- 180 19.00 19.15 a Mentioned in U. S. Patent 2,073,1000(1937). * Described in German Patent 431,166, m. p. 70". Described in U. S. Patent 1,889,645 (1932), m. p. 69-70 . Microanalyses were carried out in these Laboratories by h4iss Esther Bass and Miss Patricia Curran.
VI11 n-Propyl
esters of p-aminobenzoic acid have antisulfonamide action.2 Dimethylaminoethyl p-butylaminobenzoate (Pontocaine), another common local anesthetic, a derivative of p-butylaminobenzoic acid, also was reported to show this behavior. In the course of an investigation to determine whether N-substitution in general affects antisulfonamide action, a series of p-alkylaminobenzoic acid esters and amides was prepared; these compounds are described in Table I. These alkyl derivatives were all prepared froin the corresponding amino compounds. The Nethylaminobenzoic esters were prepared by ethylation with ethyl sulfate. Ethyl iodide was used to prepare the N-ethylaminobenzamide. This amide and the ethyl ester of p-ethylaminobenzoic acid were separated from the reaction mixture and purified by means of their nitroso derivatives. The N-propyl and n-butyl derivatives were prepared by reaction of the amino compound with the appropriate aldehyde in a reducing medium.a Attempts to prepare the amides from the alkylaminobenzoic acids by fusion and treatment with ammonia gave only the corresponding alkylanilines. The same results were obtained by heating the amino acids at 210-220'. These results can be explained when the alkylaminobenzoic acids are considered as vinylogs of carbamic acid. Bacteriological investigations indicate that whereas local anesthetics derived from p-aminobenzoic acid show marked antisulfonamide activity, the N-alkylamino derivatives, including Pontocaine, have little or no such effect. Details of this work will be published elsewhere from these Laboratories. Experimental Methyl p-Ethy1amiuobenzoate.-A mixture of 25 g. (0.165 mole) of methyl p-aminobenzoate, 25.7 g. (0.165 (2) Keltch, Baker, Krahl and Clowes, Proc. SOC.E x g f l . B i d . M e d . , 47, 533 (1941). 13) Lockemann, F i d l . , 16, 356 (1927); German Patent 491,856.
mole) of ethyl sulfate and 82.5 cc. (0.165 mole) of 2 N sodium hyaroxide was refluxed gently for twenty minutes. The solid which separated on cooling was filtered off and washed with water. The product was purified by recrystallizations from methyl alcohol. Methyl pPropy1aminobenzoate.-Eleven and one-half grams (0.198 mole) of propionaldehyde was added dropwise over a period of one and one-half hours to a well stirred refluxing mixture of 25 g. (0.165 mole) of methyl paminobenzoate, 42.5 g. (0.65 mole) of zinc dust, 40 g. (0.67 mole) of glacial acetic acid, and 130 cc. of benzene. After an additional one and one-half hours of refluxing, the benzene solution was filtered hot and dilute sodium hydroxide solution was added until the aqueous layer remained alkaline. The benzene layer was separated, dried over sodium sulfate, the benzene removed by distillation, and the residue was vacuum distilled. The product was collected at 143-1.15" (1 mm.). It was recry'stallized first fro? dilute alcohol and then from benzene and "Skellysolve A. Compounds 111, V and VI were prepared by this procedure. Ethyl pEthy1aminobenzoate.-A mixture of 82.5 g. (0.5 mole) of ethyl p-aminobenzoate, 77 g. (0.5 mole) of ethyl sulfate and 250 cc. of 2 N sodium hydroxide was refluxed for one-half hour. The oily layer was separated and dissolved in 400 cc. of dilute hydrochloric acid. To this solution, with ice cooling and stirring, was added a solution of 35 g. of sodium nitrite in 100 cc. of water. The nitroso derivative which separated was filtered off, washed with dilute hydrochloric acid and then water and dried. The product was dissolved in 600 cc. of absolute alcohol and saturated with dry hydrogen chloride. It was then refluxed for thirty minutes and most of the alcohol was distilled under reduced pressure. The hydrochloride of ethyl p-ethylarninobenzoate separated. A sample was recrystallized from a mixture of alcohol and ether; m. p. 139140'. Anal. Calcd. for C11H1INOzCl: N, 6.14. Found: N, 6.29. Water was added to the alcohol residue to dissolve the hydrochloride completely and the solution was filtered with charcoal. The base was precipitated with sodium carbonate and recrystallized from dilute alcohol. Buty1aniline.-Twenty-nine grams of p-butylaminobenzoic acid was heated in a flask a t 220' for two hours, and 40 cc. of benzene was added. After cooling, a small amount of unchanged acid was filtered off. The benzene in the filtrate was removed and the residue was vacuum distilled; b. p. 68" (1 mm.). The hydrochloride was recrystallized from ethyl acetate; m. p. 114-115". Anal. Calcd. for ClpH1aC1: N, 7.55; C1, 19.15. Found: N, 7.81; C1. 18.92.
Dec., 1944
COMMUNICATIONS TO THE EDITOR
pEthylaminobenzamide.-A mixture of 0.8 g. (0.05 mole) of p-aminobenzamide, 7.8 g. (0.05 mole) of ethyl iodide and 5 g. of sodium bicarbonate in 75 cc. of 35% aqueous alcohol was refluxed on the steam-bath for eight hours. Most of the solvent was distilled off,water added, and the solid filtered off. The product was dissolved in 70 cc. of dilute hydrochloric acid, cooled in ice water and to it, with stirring, was added a solution of 3 g. of sodium nitrite in 15 cc. of water. The nitroso derivative was filtered off, washed with water and dried; crude yield, 5.5 g. It was dissolved in 180 cc. of hot absolute alcohol and filtered with charcoal. Dry hydrogen chloride was bubbled into the cooled and well stirred filtrate a t a rapid rate until all the solid went into solution. The clear solution was stirred a t room temperature for four and onehalf hours, filtered with charcoal, and evaporated almost to dryness. Water was added to dissolve the hydrochloride
2129
which separated and the solution was made alkaline with ammonium hydroxide. On standing, the product separated out. It was recrystallized from hot Water. pPropy1aminobenzamide.-A mixture of 10.8. g. of p aminobenzamide, 60 g. of zinc dust, 100 cc. of glacial acetic acid, and 200 cc. of absolute alcohol was refluxed on a steambath with stirring. Five grams of freshly distilled propionaldehyde was added over a period of one hour and refluxing continued for one hour longer. The solid was filtered off and the filtrate was steam distilled to remove the alcohol and acetic acid. The residue (about 750 cc.) was cooled and the solid which separated was filtered off and recrystallized from dilute alcohol. Compound IX was prepared by a similar procedure. RESEARCH LABORATORIES Co., INC. WINTHROP CHEMICAL RECEIVED JUNE 9, 1944 RENSSELAER, N. Y.
COMMUNICATIONS T O T H E EDITOR THE NATURE OF CYPRIDINA LUCIFERIN
one millionth part of the light emitted by the luciferin from a small.amount of C y p r i d i ~ . ~ In Johnson and Eyring have recently stated‘ any case if reduced riboflavin is to be regarded as that “ ‘luciferin’ apparently contains both co- a substrate in the luminescent reaction identical enzyme (I or 11) and a flavin prosthetic group.” with or analogous to luciferin, the amount of light Ball and Ramsdel12 are led to “suspect that emitted should be large and should be related to flavin-adenine dinucleotide may play some role the amount of substrate oxidized. in the luminescent mechanisms of the firefly.” Indirect studies on the oxidation-reduction poSince Cypridina luciferin is oxidizableSreversibly4 tential of luciferin4 place it near toluhydroquinone this latter suggestion is a plausible possibility. and hydroquinone.a The oxidation reduction poThe more definite conclusion of Johnson and tential of riboflavin is 0.4 or 0.5 v. lower than this Eyringl is a priori a very attractive one because a t pH 7.0, while that of coenzyme is still lower. of the fundamental importance of the coenzymes It has been reported that luciferin concentrates and flavins in cellular oxidations and the occur- contain no nitrogenlg although the sensitivity of rence of flavins in a number of oxidases. Un- the method in relation to the amount of partially fortunately, a reexamination of the experimental purified luciferin was not stated. In unpublished material on luciferin does not entirely confirm experiments of Dr. M. Kunitz, attempts to meastheir conclusion. ure coenzyme I in luciferin preparations were unIn regard to the absorption spectrum of Cypri- successful. Here the sensitivity was such that dina luciferin, comparison should be made with the luciferin sample could hardly have contained the flavins rather than the flavoproteins. Oxi- as much as 2% of coenzyme. dized riboflavin has maxima a t about 3600 and The available data, therefore, although they 4500 A.6 while reduced riboflavin is colorless. may not exclude the conclusion of Johnson and Reduced luciferin concentrates show a maximum Eyring, certainly give it little support. a t about 4300 and hence, since this is probably ( 7 ) Harvey, Science, 67, 501 (1923). (8) This suggests the desirability of investiaating luciferin as a due to luciferin, it is a colored compound. This link between flavins and oxygeu. band disappears after brief aeration anq a new possible (9) Chakravorty and Ballentine, THIS J O U R N A L , 63, 2030 (1941). band appears at about 4700 A. The 4700 A. band UNIVERSITY OF MARYLAND MEDICAL SCHOOL disappears after prolonged exposure of the solution BALTIMORE, MARYLAND to air while a band at about 3600 A. appears. S. ANDERSON PRINCETON UNIVERSITY ROBERT Johnson and Eyring report’ that luminescence PRINCETON, ACRINhl. CHASE NEW JERSEY occurs after treatment of “luciferase” solution RECEIVED NOVEMBER 3, 1944 with Na&04, reduced coenzymes or riboflavin. Such an experiment is difficult to interpret if the COLORIMETRIC TESTS FOR DDT AND RELATED observed luminescence was faint. It is easily COMPOUNDS possible for the partially dark adapted eye to see Sir: (1) Johnson and Eyring, THISJOURNAL, 68, 848 (1944). The revolutionary development of the insecti(2) Ball and Ramsdell, ibid., 66, 1119 (1914). cide DDT,’ the major portion of the technical (3) Harvey, J . Ccn. P . , I, 133 (1918). product being 2,2-bis(p-chlorophenyl)-l, 1,l-tri( 4 ) Anderson, J . Cell. & Comp. Physiol., 8 , 261 (1936).
Sir:
( 5 ) Warburg and Christian, Biochcm. Z.,SSO, 150 (1938). (6) Chase, J . B i d . Chcm., 160, 433 (1943).
(1) Annand, J . ,%cow. Enlomol., ST, 125 (1944); Froelicher, Soap and Sanil. Chem., SO (7),116 (1944).
